US11091533B2ActiveUtilityA1

Protease-activated receptor-2 modulators

70
Assignee: OASIS PHARMACEUTICALS LLCPriority: Nov 13, 2015Filed: Nov 11, 2016Granted: Aug 17, 2021
Est. expiryNov 13, 2035(~9.4 yrs left)· nominal 20-yr term from priority
Inventors:Richard J. Looby
C07K 14/705A61P 37/08A61P 1/04A61P 19/02A61P 17/06A61P 3/00A61P 3/04A61K 38/00A61P 35/00A61P 29/00C07K 14/723A61P 17/04A61P 17/00A61P 11/00A61P 13/12A61P 35/02A61P 3/10A61P 9/12A61P 1/16A61P 3/06A61P 31/04
70
PatentIndex Score
1
Cited by
105
References
95
Claims

Abstract

Provided herein are peptides comprising a mutated fragment of a wild-type protease-activated receptor-2 (PAR2). The peptides comprising a hydrophobic moiety can penetrate the cell membrane and act as an antagonist of PAR2. Also provided herein are compositions and cells comprising the peptides and methods of using the peptides.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. A peptide comprising a sequence of:
 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20  (SEQ ID NO: 42), wherein: 
 X 4  is absent, A, G, P, eK, or aminohexanoic acid (Ahx); 
 X 5  is M, G, P, I, L, V, norleucine (J), methionine sulfoxide (M(SO)), or methionine sulfone (M(SO 2 )), or absent when X 4  is absent; 
 X 6  is D, E, H, or absent when X 4  to X 5  are absent; 
 X 7  is D, E, H, or absent when X 4  to X 6  are absent; 
 X 8  is N, D, or E; 
 X 9  is any amino acid; 
 X 10  is any amino acid; 
 X 11  is any amino acid or D-amino acid thereof, 2-aminoisobutyric acid (B), hydroxyproline (Hyp), P, a proline homolog, G, W, N, an amino acid with a methyl-amino group at the peptide bond, 1-aminocyclopropanecarboxylic acid (ACC), para-aminobenzoic acid (Paba), or an alpha-substituted tyrosine analog; 
 X 12  is K, R, or P; 
 X 13  is R, F, W, Y, or citrulline (Cit); 
 X 14  is K or any amino acid that makes the peptide bond between X 13  and X 14  uncleavable by a protease, D, E, A, S, V, L, I, P, F, W, M, G, T, C, Y, N, or Q; 
 X 15  is Q, N, H, S, T, Y, C, M, W, or beta-A; 
 X 16  is A, S, T, G, Q, beta-A,  2 -aminoisobutyric acid (B), or absent; 
 X 17  is I, A, L, or V; 
 X 18  is K, I, or F; 
 X 19  is dA or G, P, I, L, V, F, K, or a D-amino acid thereof; and 
 X 20  is a hydrophobic amino acid, a D-amino acid thereof, any amino acid that makes the peptide bond between X 19  and X 20  uncleavable by a protease, or absent; and 
 the peptide comprises a hydrophobic moiety, and the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: capryloyl (C 8 ); nonanoyl (C 9 ); capryl (C 10 ); 
 undecanoyl (C 11 ); lauroyl (C 12 ); tridecanoyl (C 13 ); myristoyl (C 14 ); pentadecanoyl (C 15 ); palmitoyl (C 16 ); phytanoyl (methyl substituted (C 16 ); heptadecanoyl (C 17 ); stearoyl (C 18 ); nonadecanoyl (C 19 ); arachidoyl (C 20 ); heneicosanoyl (C 21 ); behenoyl (C 22 ); trucisanoyl (C 23 ); and lignoceroyl (C 24 ). 
 
     
     
       2. The peptide of  claim 1 , wherein X 9  is S, T, H, R, or K; X 10  is E or D; and X 18  is K, I, or F. 
     
     
       3. The peptide of  claim 1  comprising the sequence of:
 X 4 X 5 X 6 X 7 X 8 SEX 11 X 12 X 13 X 14 X 15 X 16 X 17 KX 19  (SEQ ID NO: 43), wherein: 
 X 4  is absent, A, G, P, eK, or aminohexanoic acid (Ahx); 
 X 5  is M, G, P, I, L, V, norleucine (J), methionine sulfoxide (M(SO)), or methionine sulfone (M(SO 2 )), or absent when X 4  is absent; 
 X 6  is D, E, H, or absent when X 4  to X 5  are absent; 
 X 7  is D, E, H, or absent when X 4  to X 6  are absent; 
 X 8  is N, D, or E; 
 X 11  is any amino acid or D-amino acid thereof,  2 -aminoisobutyric acid (B), hydroxyproline (Hyp), P, a proline homolog, G, W, N, an amino acid with a methyl-amino group at the peptide bond,  1 -aminocyclopropanecarboxylic acid (ACC), para-aminobenzoic acid (Paba), or an alpha-substituted tyrosine analog; 
 X 12  is K, R, or P; 
 X 13  is R, F, W, Y, or citrulline (Cit); 
 X 14  is K or any amino acid that makes the peptide bond between X 13  and X 14  uncleavable by a protease, D, E, A, S, V, L, I, P, F, W, M, G, T, C, Y, N, or Q; 
 X 15  is Q, N, H, S, T, Y, C, M, W, or beta-A; 
 X 16  is A, S, T, G, Q, beta-A,  2 -aminoisobutyric acid (B), or absent; 
 X 17  is I, A, L, or V; and 
 X 19  is dA or G, P, I, L, V, F, K, or a D-amino acid thereof. 
 
     
     
       4. The peptide of  claim 1 , wherein X 11  is K. 
     
     
       5. The peptide of  claim 1 , wherein X 4  is selected from the group consisting of eK, aminohexanoic acid (Ahx), P, or G. 
     
     
       6. The peptide of  claim 1 , wherein the peptide further comprises X 3  at the N-terminus, wherein X 3  is S, G, P, eK, aminohexanoic acid (Ahx), W, N, an amino acid with a methyl-amino group at the peptide bond, 1-aminocyclopropanecarboxylic acid (ACC), para-aminobenzoic acid (Paba), or an alpha-substituted tyrosine analog. 
     
     
       7. A peptide comprising a sequence selected from the group consisting of SEQ ID NOs: 42-68 with zero or 1 amino acid change, wherein the change is an amino acid substitution, deletion, and/or addition, wherein positions X 1 to X 20  correspond to positions  270  to  289  of the human PAR 2  sequence, and wherein:
 X 1  is absent, R, or K; 
 X 2  is absent when X 1  is absent, S, or T; 
 X 3  is absent when X 1  to X 2  are absent, S, G, P, eK, aminohexanoic acid (Ahx), W, N, an amino acid with a methyl-amino group at the peptide bond, 1-aminocyclopropanecarboxylic acid (ACC), para-aminobenzoic acid (Paba), or an alpha-substituted tyrosine analog; 
 X 4  is absent when Xi to X 3  are absent, A, G, P, eK, or aminohexanoic acid (Ahx); 
 X 5  is M, G, P, I, L, V, norleucine (J), methionine sulfoxide (M(SO)), or methionine sulfone (M(SO 2 )), or absent when X 1  to X 4  are absent; 
 X 6  is D, E, H, or absent when X 1  to X 5  are absent; 
 X 7  is D, E, H, or absent when X 1  to X 6  are absent; 
 X 8  is N, D, or E; 
 X 9  is any amino acid; 
 X 10  is any amino acid; 
 X 11  is K, dK, 2-aminoisobutyric acid (B), hydroxyproline (Hyp), P, dP, G, W, dW, N, or dN; 
 X 12  is K, R, P; or absent; 
 X 13  is any amino acid or citrulline (Cit); 
 X 14  is K or any amino acid that makes the peptide bond between X 13  and X 14  uncleavable by a protease, D, E, A, S, V, L, I, P, F, W, M, G, T, C, Y, N, or Q; 
 X 15  is Q, N, H, S, T, Y, C, M, W, or beta-A; 
 X 16  is A, S, T, G, Q, beta-A, 2-aminoisobutyric acid (B), or absent; 
 X 1   7  is I, A, L, or V; 
 X 18  is K, I, or F; 
 X 19  is dA or G, P, I, L, V, F, K, or a D-amino acid thereof; and 
 X 20  is a hydrophobic amino acid, a D-amino acid thereof, any amino acid that makes the peptide bond between X 19  and X 20  uncleavable by a protease, or absent; 
 provided that the peptide is at most 30 amino acids in length; and 
 the peptide comprises a hydrophobic moiety, and the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: capryloyl (C 8  ); nonanoyl (C 9 ); capryl (C 10 ); undecanoyl (C 11 ); lauroyl (C 12 ); tridecanoyl (C 13 ); myristoyl (C 14 ); pentadecanoyl (C 15 ); palmitoyl (C 16 ); phytanoyl (methyl substituted C 16 ); heptadecanoyl (C 17 ); stearoyl (C 18 ); nonadecanoyl (C 19 ); arachidoyl (C 20 ); heneicosanoyl (C 21 ); behenoyl (C 22 ); trucisanoyl (C 23 ); and lignoceroyl (C 24 ). 
 
     
     
       8. The peptide of  claim 7 , wherein the peptide comprises the sequence of X 4 X 5 X 6 X 7 X 8 SEX 11 X 12 X 13 X 14 X 15 X 16 X 17 KX 19  (SEQ ID NO: 43). 
     
     
       9. A peptide comprising a mutated fragment of human wild-type PAR 2  protein, wherein the peptide shares, in sequence and position, at least two sections each with at least two contiguous amino acid residues within amino acid residues 270-290 of the human wild-type PAR2 sequence, comprising a first section of at least two contiguous amino acid residues of the human wild-type PAR2 sequence, and comprising a second section of at least three contiguous amino acid residues of the human wild-type PAR2 sequence, wherein the first section and the second section are separated by at least one amino acid that is different from a residue found at the corresponding position of a human wild-type PAR2 sequence;
 the amino acid at the position corresponding to position 287 of the human wild-type PAR2 sequence is K, I, or F; and 
 the amino acid at the position corresponding to position 288 of the human wild-type PAR2 sequence is L, dV, K, or dA; and 
 the peptide comprises a hydrophobic moiety, and the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: capryloyl (C 8 ); nonanoyl (C 9 ); capryl (C 10 ); undecanoyl (C 11 ); lauroyl (C 12 ); tridecanoyl (C 13 ); myristoyl (C 14 ); pentadecanoyl (C 15 ); palmitoyl (C 16 ); phytanoyl (methyl substituted (C 16 ); heptadecanoyl (C 17 ); stearoyl (C 18 ); nonadecanoyl (C 19 ); arachidoyl (C 20 ); heneicosanoyl (C 21 ); behenoyl (C 22 ); trucisanoyl (C 23 ); and lignoceroyl (C 24 ). 
 
     
     
       10. A peptide comprising a mutated fragment of human wild-type PAR2 protein, wherein the peptide shares, in sequence and position, at least two sections each with at least four contiguous amino acid residues within amino acid residues 270-290 of the human wild-type PAR2 sequence, wherein the two sections are separated by at least one amino acid that is different from a residue found at the corresponding position of a human wild-type PAR2 sequence;
 and the amino acid at the position corresponding to position 288 of the human wild-type PAR2 sequence is V, L, K, dl, dV, or dA; and 
 the peptide comprises a hydrophobic moiety, and the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: capryloyl (C 8  ); nonanoyl (C 9 ); capryl (C 10 ); undecanoyl (C 11 ); lauroyl (C 12 ); tridecanoyl (C 13 ); myristoyl (C 14 ); pentadecanoyl (C 15 ); palmitoyl (C 16 ); phytanoyl (methyl substituted C 16 ); heptadecanoyl (C 17 ); stearoyl (C 18 ); nonadecanoyl (C 19 ); arachidoyl (C 20 ); heneicosanoyl (C 21 ); behenoyl (C 22 ); trucisanoyl (C 23 ); and lignoceroyl (C 24 ). 
 
     
     
       11. The peptide of  claim 1 , wherein the peptide comprises a consensus sequence DEN at positions corresponding to positions 275-277, wherein X 6  is D, X 7  is E, and X 8  is N of the human PAR2 sequence. 
     
     
       12. The peptide of  claim 1 , wherein the peptide is 11-30 amino acids in length. 
     
     
       13. A pharmaceutical composition comprising a peptide of  claim 1 . 
     
     
       14. The peptide of  claim 1 , wherein X 4  is A, G, P, eK, or Ahx. 
     
     
       15. The peptide of  claim 1 , wherein X 5  is M, G, P, I, or L. 
     
     
       16. The peptide of  claim 1 , wherein X 6  is D, E, or H. 
     
     
       17. The peptide of  claim 1 , wherein X 7  is E or H. 
     
     
       18. The peptide of  claim 1 , wherein X 8  is N or D. 
     
     
       19. The peptide of  claim 1 , wherein X 9  is S or H. 
     
     
       20. The peptide of  claim 1 , wherein X 10  is E. 
     
     
       21. The peptide of  claim 1 , wherein X 11  is K, 2-aminoisobutyric acid (B), hydroxyproline (Hyp), P, dP, G, W, or N. 
     
     
       22. The peptide of  claim 1 , wherein X 12  is K or P. 
     
     
       23. The peptide of  claim 1 , wherein X 14  is K, dK, L, I , or V. 
     
     
       24. The peptide of  claim 1 , wherein X 15  is beta-A, Q, S, or W. 
     
     
       25. The peptide of  claim 1 , wherein X 16  is A, 2-aminoisobutyric acid (B), Q, or absent. 
     
     
       26. The peptide of  claim 1 , wherein X 17  is I or A. 
     
     
       27. The peptide of  claim 1 , wherein X 18  is K or I. 
     
     
       28. The peptide of  claim 1 , wherein X 19  is G, P, I, L, V, F, K, or a D-amino acid thereof. 
     
     
       29. The peptide of  claim 1 , wherein X 19  is L, I, V, K, dA, dL, dI, or dV. 
     
     
       30. The peptide of  claim 1 , wherein X 20  is G, P, A, I, L, V, F, or a D-amino acid thereof. 
     
     
       31. The peptide of  claim 30 , wherein X 20  is L, I, V, dL, dl, or dV. 
     
     
       32. The peptide of  claim 1 , wherein the peptide is 13-18 amino acids in length. 
     
     
       33. The peptide of  claim 32 , wherein the peptide is 15-18 amino acids in length. 
     
     
       34. The peptide of  claim 1 , wherein X 15  is S; X 16  is A; X 17  is I; and X 18  is K. 
     
     
       35. The peptide of  claim 1 , wherein X 15  is Q; X 16  is A; X 17  is I; and X 18  is K. 
     
     
       36. The peptide of  claim 1 , wherein X 16  is A; X 17  is I; X 15  is K; and X 19  is L. 
     
     
       37. The peptide of  claim 1 , wherein the peptide comprises the sequence of SEQ ID NO: 9. 
     
     
       38. The peptide of  claim 1 , wherein X 14  is a D-amino acid, an amino acid with an N-methyl at the peptide bond, A, S, V, L, I, P, F, W, M, G, T, C, Y, N, Q, D, or E. 
     
     
       39. The peptide of  claim 1 , wherein the peptide comprises the sequence of SEQ ID NO: 11. 
     
     
       40. The peptide of  claim 1 , wherein the peptide comprises the sequence of SEQ ID NO: 13. 
     
     
       41. The peptide of  claim 1 , wherein the peptide comprises the sequence of SEQ ID NO: 15. 
     
     
       42. The peptide of  claim 1 , wherein the peptide comprises the sequence of SEQ ID NO: 9; and the hydrophobic moiety is palmitoyl (C 16 ) which is attached to the N-terminus of the peptide. 
     
     
       43. The peptide of  claim 1 , wherein the peptide comprises the sequence of SEQ ID NO: 11; and the hydrophobic moiety is palmitoyl (C 16 ) which is attached to the N-terminus of the peptide. 
     
     
       44. The peptide of  claim 1 , wherein the peptide comprises the sequence of SEQ ID NO: 13; and the hydrophobic moiety is palmitoyl (C 16 ) which is attached to the N-terminus of the peptide. 
     
     
       45. The peptide of  claim 1 , wherein the peptide comprises the sequence of SEQ ID NO: 15; and the hydrophobic moiety is palmitoyl (C 16 ) which is attached to the N-terminus of the peptide. 
     
     
       46. A peptide comprising a sequence of:
 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20  (SEQ ID NO: 42), wherein: 
 X 4  is absent, A, G, P, eK, or aminohexanoic acid (Ahx); 
 X 5  is M, G, P, I, L, V, norleucine (J), methionine sulfoxide (M(SO)), or methionine sulfone (M(SO 2 )), or absent when X 4  is absent; 
 X 6  is D, E, H, or absent when X 4  to X 5  are absent; 
 X 7  is D, E, H, or absent when X 4  to X 6  are absent; 
 X 8  is N, D, or E; 
 X 9  is any amino acid; 
 X 10  is any amino acid; 
 X 11  is K, dK, 2-aminoisobutyric acid (B), hydroxyproline (Hyp), P, dP, G, W, dW, N, or dN; 
 X 12  is K, R, or P; 
 X 13  is R, F, W, Y, or citrulline (Cit); 
 X 14  is K or any amino acid that makes the peptide bond between X 13  and X 14  uncleavable by a protease, D, E, A, S, V, L, I, P, F, W, M, G, T, C, Y, N, or Q; 
 X 15  is Q, N, H, S, T, Y, C, M, W, or beta-A; 
 X 16  is A, S, T, G, Q, beta-A, 2-aminoisobutyric acid (B), or absent; 
 X 1   7  is I, A, L, or V; 
 X 18  is K, I, or F; 
 X 19  is dA or G, P, I, L, V, F, K, or a D-amino acid thereof; and 
 X 20  is a hydrophobic amino acid, a D-amino acid thereof, any amino acid that makes the peptide bond between X 19  and X 20  uncleavable by a protease, or absent; and 
 the peptide comprises a hydrophobic moiety, and the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: capryloyl (C 8 ); nonanoyl (C 9 ); capryl (C 10 ); 
 undecanoyl (C 11 ); lauroyl (C 12 ); tridecanoyl (C 13 ); myristoyl (C 14 ); pentadecanoyl (C 15 ); palmitoyl (C 16 ); phytanoyl (methyl substituted C 16 ); heptadecanoyl (C 17 ); stearoyl (C 18 ); nonadecanoyl (C 19 ); arachidoyl (C 20 ); heneicosanoyl (C 21 ); behenoyl (C 22 ); trucisanoyl (C 23 ); and lignoceroyl (C 24 ). 
 
     
     
       47. The peptide of  claim 46 , wherein the peptide is at most 25 amino acids in length. 
     
     
       48. The peptide of  claim 46 , wherein the peptide is at most 20 amino acids in length. 
     
     
       49. A peptide comprising a sequence selected from the group consisting of SEQ ID NOs: 3, 5-30, 32, 33, 35, 37, 39, and 41 with zero or 1 amino acid change, wherein the change is an amino acid substitution, deletion, and/or addition. 
     
     
       50. The peptide of  claim 49 , wherein the peptide comprises a hydrophobic moiety. 
     
     
       51. The peptide of  claim 49 , wherein the peptide is at most 25 amino acids in length. 
     
     
       52. The peptide of  claim 49 , wherein the peptide is at most 20 amino acids in length. 
     
     
       53. The peptide of  claim 6 , wherein X 3  is selected from the group consisting of eK, aminohexanoic acid (Ahx), P, G, W, and N. 
     
     
       54. The peptide of  claim 7 , wherein the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: myristoyl (C 14 ) and palmitoyl (C 16 ). 
     
     
       55. The peptide of  claim 7 , wherein the peptide is at most 25 amino acids in length. 
     
     
       56. The peptide of  claim 7 , wherein the peptide is at most 20 amino acids in length. 
     
     
       57. The peptide of  claim 9 , wherein the peptide comprises at least one mutation at the amino acid position 273, 274, 275, 276, or 277 of the human PAR2 sequence. 
     
     
       58. The peptide of  claim 9 , wherein the peptide comprises at least one mutation at the amino acid position 273, 274, 282, or 284 of the human PAR2 sequence. 
     
     
       59. The peptide of  claim 9 , wherein the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: myristoyl (C 14 ) and palmitoyl (C 16 ). 
     
     
       60. The peptide of  claim 9 , wherein the peptide is at most 25 amino acids in length. 
     
     
       61. The peptide of  claim 10 , wherein the peptide is at most 20 amino acids in length. 
     
     
       62. The peptide of  claim 10 , wherein the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: myristoyl (C 14 ) and palmitoyl (C 16 ). 
     
     
       63. The peptide of  claim 10 , wherein the peptide is at most 25 amino acids in length. 
     
     
       64. The peptide of  claim 10 , wherein the peptide is at most 20 amino acids in length. 
     
     
       65. The peptide of  claim 7 , wherein the peptide is the sequence selected from the group consisting of SEQ ID NOs: 42-68 with zero amino acid changes. 
     
     
       66. A peptide of the sequence selected from the group consisting of SEQ ID NOs: 1-37 and 39-41 with zero amino acid changes. 
     
     
       67. The peptide of  claim 53 , wherein X 3  is eK. 
     
     
       68. The peptide of  claim 1 , wherein the peptide comprises a consensus sequence HHD at positions corresponding to positions 275-277, wherein X 6  is H, X 7  is H, and X 8  is D of the human PAR2 sequence. 
     
     
       69. The peptide of  claim 7 , wherein the peptide comprises a consensus sequence DEN at positions corresponding to positions 275-277, wherein X 6  is D, X 7  is E, and X 8 is N of the human PAR2 sequence. 
     
     
       70. The peptide of  claim 7 , wherein the peptide comprises a consensus sequence HHD at positions corresponding to positions 275-277, wherein X 6  is H, X 7  is H, and X 8  is D of the human PAR2 sequence. 
     
     
       71. The peptide of  claim 49 , wherein the peptide comprises a hydrophobic moiety that comprises a lipid moiety selected from the group consisting of: capryloyl (C 8 ); nonanoyl (C 9 ); capryl (C 10 ); undecanoyl (C 11 ); lauroyl (C 13 ); tridecanoyl (C 13 ); myristoyl (C 14 ); pentadecanoyl (C 15 ); palmitoyl (C 6 ); phytanoyl (methyl substituted C 16 ); heptadecanoyl (C 15 ); stearoyl (C 18 ); nonadecanoyl (C 19 ); arachidoyl (C 20 ); heneicosanoyl (C 21 ); behenoyl (C 22 ); trucisanoyl (C 23 ); and lignoceroyl (C 24 ). 
     
     
       72. The peptide of  claim 71 , wherein the hydrophobic moiety is attached to the N-terminus of the peptide. 
     
     
       73. The peptide of  claim 10 , wherein the peptide comprises at least one mutation at the amino acid position corresponding to position 273, 274, 275, 276, 277, 282, or 284 of the human PAR2 sequence. 
     
     
       74. The peptide of  claim 10 , wherein:
 the amino acid position corresponding to position 273 is A, eK, aminohexanoic acid (Ahx), P, or G; 
 the amino acid position corresponding to position 274 is M, G, P, I, L, V, norleucine (J), M(SO), or M(SO 2 ); 
 the amino acid position corresponding to position 275 is D, E, or H; 
 the amino acid position corresponding to position 276 is D, E, or H; and 
 the amino acid position corresponding to position 277 is D, E, or N. 
 
     
     
       75. The peptide of  claim 1 , wherein the hydrophobic moiety is attached to the N-terminus of the peptide. 
     
     
       76. The peptide of  claim 7 , wherein the hydrophobic moiety is attached to the N-terminus of the peptide. 
     
     
       77. The peptide of  claim 59 , wherein the hydrophobic moiety is attached to the N-terminus of the peptide. 
     
     
       78. The peptide of  claim 62 , wherein the hydrophobic moiety is attached to the N-terminus of the peptide. 
     
     
       79. A pharmaceutical composition comprising a peptide of  claim 7 . 
     
     
       80. A pharmaceutical composition comprising a peptide of  claim 9 . 
     
     
       81. A pharmaceutical composition comprising a peptide of  claim 10 . 
     
     
       82. A pharmaceutical composition comprising a peptide of  claim 49 . 
     
     
       83. The peptide of  claim 50 , wherein the peptide comprises the sequence selected from the group consisting of SEQ ID NOs: 3, 5-30, 32, 33, 35-37, 39, and 41. 
     
     
       84. The peptide of  claim 46 , wherein the hydrophobic moiety is attached to the N-terminus of the peptide. 
     
     
       85. The peptide of  claim 46 , wherein the hydrophobic moiety comprises a lipid moiety selected from the group consisting of: myristoyl (C 14 ) and palmitoyl (C 16 ). 
     
     
       86. The peptide of  claim 85 , wherein the hydrophobic moiety comprises palmitoyl (C 16 ). 
     
     
       87. The peptide of  claim 7 , wherein X 9  is S, T, H, R, or K; and X 11  is E or D. 
     
     
       88. The peptide of  claim 7 , wherein X 11  is K or P. 
     
     
       89. The peptide of  claim 7 , wherein X 12  is K or P. 
     
     
       90. The peptide of  claim 7 , wherein X 14  is K, dK, L, I, or V. 
     
     
       91. The peptide of  claim 9 , wherein:
 the amino acid position corresponding to position 273 is A, eK, aminohexanoic acid (Ahx), P, or G; 
 the amino acid position corresponding to position 274 is M, G, P, I, L, V, norleucine (J), M(SO), or M(SO 2 ); 
 the amino acid position corresponding to position 275 is D, E, or H; 
 the amino acid position corresponding to position 276 is D, E, or H; and 
 the amino acid position corresponding to position 277 is D, E, or N. 
 
     
     
       92. The peptide of  claim 9 , wherein the amino acid position corresponding to position 280 is K, 2-aminoisobutyric acid (B), hydroxyproline (Hyp), P, dP, G, W, or N. 
     
     
       93. The peptide of  claim 9 , wherein the amino acid position corresponding to position 280 is K or P. 
     
     
       94. The peptide of  claim 10 , wherein the amino acid position corresponding to position 280 is K, 2-aminoisobutyric acid (B), hydroxyproline (Hyp), P, dP, G, W, or N. 
     
     
       95. The peptide of  claim 46 , wherein X 9  is S, T, H, R, or K; and X 10  is E or D.

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